L723P
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialLeucine → Proline at position 723 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.959, DynaMut2 ΔΔG -0.19 kcal/mol (destabilising). Another proline-introduction variant in the lumenal fold.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I720 | I720 | Preserved |
| Polar contact | — | A719 | Gained |
| Polar contact | I720 | I720 | Preserved |
| Van der Waals | — | I720 | Gained |
| Van der Waals | N721 | — | Lost |
| Hydrophobic | I727 | I727 | Preserved |
| Hydrophobic | M731 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
Position 723 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L723 within 5 Å of MET722 (2.5 Å), PRO724 (2.5 Å), ILE720 (3.6 Å), ASN721 (4.6 Å), and ALA719 (4.8 Å). The local environment is hydrophobic-rich (M722, I720, A719) with a single polar residue (N721). Notably, PRO724 sits at 2.5 Å — the immediate downstream neighbor is already a proline.
Replacing L723 with proline introduces a second proline immediately adjacent to the existing P724 — a Pro-Pro motif is unusual and structurally distinctive. Two adjacent prolines create a particularly rigid backbone segment with restricted conformational options. The wild-type Leu-Pro motif at 723-724 transitions from flexible to constrained backbone; the variant Pro-Pro motif is constrained on both sides.
The |ΔΔG| of 0.19 is modest — the fold absorbs the new proline because the local environment was already constrained. But the geometry shifts: the Pro-Pro motif likely adopts a different local conformation than the wild-type Leu-Pro, and surrounding residues (M722, I720) rearrange to accommodate.
AlphaMissense's 0.959 score captures the functional severity — the shifted local geometry disrupts whatever interaction the wild-type Leu-Pro motif enabled.
Druggability Assessment
The mechanism is creation of an unusual Pro-Pro motif at positions 723-724, shifting the local backbone geometry from a Leu-Pro transition to a rigid Pro-Pro segment. Therapeutic strategy: site-directed small molecules at the position 720-724 region, ideally compensating for the geometric shift.
This is one of several proline-introduction variants in the Atlas (L402P, L543P, L723P, L804P). The therapeutic vocabulary across this class is consistent: stabilize local backbone geometry against the introduced proline kink.
Why this matters
Feed this card to Wolfram Intelligence
Download the L723P PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.